Programmed cell death or apoptosis is a cellular “suicidal” program, which can remove damaged or cancerous cells from a human body and maintain normal tissue homeostasis. There are several key components regulating the death program and maintaining a good balance of cell survival verse death. The Bcl-2 family is the most well documented family that contains both pro-death and anti-death molecules. The anti-death molecule, such as Bcl-2 functions as oncogene, while pro-death molecule, such as Bax is served as a tumor suppressor. The ratio of Bcl-2 and Bax often dictates the chemo-sensitivities in cancer treatment.
The Bax gene has six exons. Exon 3 has a microsatellite consisting of a cluster of 8 guanines (G8) stretch, which is susceptible to mutation in tumors due to microsatellite instability (MSI). A single nucleotide deletion in the Bax G8 microsatellite tract, i.e., G8 to G7, causes a reading frameshift and disruption of the nature translational reading frame and premature termination of Bax protein translation. Bax is one of the first affected genes identified in MSI tumors and found in over 50% of a set of MSI colon cancer tumors. Such tumors with reading frameshift mutations of Bax are typically considered “Bax-negative”.
RNA alternative splicing is a regulated process by which different form of mRNAs are generated from a single gene. Bax gene can generate several viable isoforms, which participate in apoptotic pathway. However, aberrant alternative splicing Bax exon 2 results in a disruption of Bax open reading frame and produces no functional viable Bax protein.